前列腺癌：间歇雄激素抑制不逊持续治疗

《新英格兰医学杂志》(New England Journal of Medicine)9月6日发表的一项研究表明，对于根治性放疗后前列腺特异性抗原(PSA)水平升高的前列腺癌患者，间歇性雄激素抑制治疗在延长患者生存期方面并不劣于持续性雄激素抑制治疗。

这项加拿大国家癌症研究所(NCIC)Ⅲ期临床试验共纳入了1,386例在接受直接或补救性放疗1年以后PSA水平仍高于3 ng/ml的局限性前列腺癌患者，其中696例被随机分配至接受持续性雄激素抑制治疗，包括促黄体激素释放激素激动剂(LHRHa)以及非类固醇类抗雄激素药物至少使用4周或者接受睾丸切除术。另外690例患者则被随机分配至接受间歇性雄激素阻断治疗，每8个月为1个治疗周期，期间根据PSA水平来确定是否给予治疗。每个治疗周期从LHRHa注射剂给药开始，并结合非类固醇类抗雄激素药物至少使用4周，如果没有证据提示临床疾病进展或者患者的PSA水平低于4 ng/ml且较之前一次测值升高不超过1 ng/ml，则在8个月后停止治疗。

作为该试验的主要研究者，加拿大不列颠哥伦比亚省癌症机构的Juanita M. Crook博士报告称，治疗期间，只要没有证据提示疾病进展，则每2个月监测1次PSA水平直至其达到10 ng/ml。这项研究的主要终点是总生存期，次要终点是患者出现去势抵抗性疾病的时间以及生活质量。间歇性治疗组患者的其他终点还包括不治疗间期的持续时间、睾酮水平恢复的时间以及性功能恢复的时间。

在为期6.9年的中位随访期内，524例患者死亡，间歇性治疗组和持续性治疗组分别有268例和256例。两组患者的中位总生存期在统计学上具有相似性，间歇性治疗组和持续性治疗组分别为8.8年和9.1年。作者写道：“间歇性治疗组与持续性治疗组的死亡危险比为1.02”，非劣性P值为.009，证实了研究者最初的假设，即间歇性治疗不劣于持续性治疗。此外，持续性治疗组因其他原因导致的死亡发生率高于间歇性治疗组，但差异无统计学意义。

鉴于大部分死亡(59%)都与前列腺癌无关，因此研究者回顾性地分析了疾病特异性生存期“以确定治疗效应上的显著差异是否被前列腺癌以外的其他死因数据所掩盖”。经分层和混杂因素校正之后，疾病特异性危险比估值为1.23，间歇性治疗组和持续性治疗组的7年累计疾病相关死亡率估值分别为18%和15%。

就患者出现去势抵抗性疾病的时间而言，经分层和预后因素校正之后的Cox回归分析表明，间歇性治疗组与持续性治疗组的危险比估值为0.81。不过，作者也指出，试验设计可能对持续性雄激素抑制治疗造成了“程度未知”的偏倚。研究者写道：“对于间歇性治疗组患者，去势抵抗性疾病的识别时间本身就存在一定程度的延迟，因为这组患者必须重新开始治疗并且睾酮水平必须达到‘去势范围’且PSA水平再升高3次才能被视为出现了去势抵抗性疾病。”

作者报告称，在生活质量指标方面，间歇性治疗组的功能性评分(生理、角色和整体健康状况)优于持续性治疗组，但差异无统计学意义；症状评分则显著优于持续性治疗组，包括热潮红、性欲和泌尿症状。间歇性治疗组有35%的患者睾酮水平完全恢复，79%恢复至入组试验时的基线值。

这项NCIC试验的结果与今年6月美国临床肿瘤学会(ASCO) 2012年会上报告的另一项国际性Ⅲ期西南肿瘤组(SWOG)9346临床试验的结果相矛盾，因此不仅不会解决反而会使有关雄激素拮抗剂内分泌治疗的合理使用和使用时机的长期争论愈演愈烈。

作者总结道，这项试验“提出了有争议的问题”，同时也提醒道该试验结果“不能外推至其他间歇性治疗方案或其他疾病特征”。这篇文章并没有提到其试验结果与SWOG 9346试验结果明显矛盾的问题。

SWOG 9346试验共纳入了3,040例新近诊断为激素敏感性转移性前列腺癌的患者，雄激素阻断前所有患者的PSA水平均大于或等于5 ng/mL，SWOG体能状态评分为0~2分，患者被随机分配至接受间歇性治疗或者持续性治疗。结果显示，间歇性治疗组的相对死亡风险增加了9%，没有达到事先确定的非劣性标准。不过，SWOG 9346数据的次要分析表明，对于广泛性疾病而非微小疾病的患者，间歇性治疗的确不劣于持续性雄激素阻断治疗。

这项NCIC试验由加拿大癌症学会、美国国立癌症研究所以及Hoeschst Marion Roussel加拿大研究机构提供的经费资助。Crook博士声明无相关经济利益冲突。其他研究者声明与多家企业之间存在经济利益关系。

随刊述评：哪些患者确实受益了？

美国新奥尔良图兰癌症中心医疗主任/图兰大学癌症研究所C.E.和 Bernadine Laborde教授Oliver Sartor博士将这项试验称作是“迄今为止在非转移性癌症患者中比较间歇性与持续性雄激素阻断治疗的最具决定性意义的一项研究”。

不过，Sartor博士也指出还有一个重要问题仍然没有得到解答：“我们还是不清楚哪些PSA水平升高的患者需要接受治疗。这是一个具有异质性的患者人群，只有一小部分患者会因PSA水平升高而出现相应的临床后果。”鉴于前列腺癌通常进展缓慢，那么“到底哪些无症状性患者能从雄激素阻断治疗中切实受益呢？”(N. Engl. J. Med. 2012;367:945-6)。

Sartor博士声明与Tolmar公司之间存在经济利益关系。

爱思唯尔版权所有  未经授权请勿转载

By: DIANA MAHONEY, Internal Medicine News Digital Network

Intermittent androgen deprivation was not associated with inferior survival for men with a rising prostate-specific antigen level after definitive radiotherapy in a study reported in the Sept. 6 issue of the New England Journal of Medicine.

The findings from the phase III National Cancer Institute of Canada (NCIC) Clinical Trials Group study appear to conflict with those of another international phase III clinical trial reported in June at the annual meeting of the American Society of Clinical Oncology, and as such may fuel rather than extinguish the longstanding debate regarding the proper use and timing of endocrine therapy with androgen antagonists.

In the NCIC trial, 696 of 1,386 men with a PSA level greater than 3 ng/mL more than 1 year after primary or salvage radiotherapy for localized prostate cancer were randomized to continuous androgen suppression therapy consisting of a luteinizing hormone–releasing hormone agonist (LHRHa), combined with a minimum of 4 weeks of a nonsteroidal antiandrogen, or orchiectomy.

Another 690 men were randomized to intermittent androgen deprivation in 8-month cycles, with periods of nontreatment determined by PSA level. Each treatment cycle for the latter group began with the administration of LHRHa injections combined with a nonsteroidal antiandrogen for a minimum of 4 weeks and ended after 8 months if there was no evidence of clinical disease progression and if the patient’s PSA level was less than 4 ng/mL and not more than 1 ng/mL above the previous recorded value.

"During the treatment interval, the PSA level was monitored every 2 months until it reached 10 ng/mL, provided there was no intervening evidence of disease progression," stated lead investigator Dr. Juanita M. Crook of the British Columbia Cancer Agency, Kelowna, and her colleagues. (N. Engl. J. Med. 2012;367:895-903).

Overall survival was the primary end point of the study, and time to castration-resistant disease and quality of life were secondary end points, the authors wrote. Duration of off-treatment intervals, time to testosterone recovery, and time to potency recovery were additional end points for patients randomized to intermittent therapy.

At a median follow-up of 6.9 years, 524 patients had died, including 268 in the intermittent group and 256 in the continuous group, the authors reported. Median overall survival in both arms was statistically similar, at 8.8 years in the intermittent group and 9.1 years in the continuous therapy group.

"The hazard ratio for death with intermittent therapy versus continuous therapy was 1.02," the authors wrote, and the P value for noninferiority, at.009, supported the investigators’ initial hypothesis that intermittent therapy was not inferior to continuous therapy. A nonsignificant increase in deaths from other causes was observed in the continuous therapy group.

Because most of the deaths (59%) were unrelated to prostate cancer, the investigators retrospectively analyzed disease-specific survival "to determine whether a significant difference in treatment effect was obscured by the data on deaths from causes other than prostate cancer," they said. The estimated disease-specific hazard ratio after adjustment for stratification and confounding factors was 1.23, and the estimated 7-year cumulative disease-related death rates were 18% and 15%, respectively, for the intermittent and continuous groups.

With respect to time to castration-resistant disease, based on a Cox regression analysis adjusted for stratification and prognostic factors, the estimated hazard ratio for intermittent versus continuous therapy was 0.81, the authors reported, noting, however, that the study design contributed to a bias "by an unknown magnitude" against continuous androgen-deprivation therapy.

"For patients in the intermittent-therapy group, there was an inherent delay in the identification of castration-resistant disease, because treatment had to be restarted in these patients and they had to have a ‘castrate-range’ testosterone level and an additional three increases in the PSA level before being classified as having castration-resistant disease," the investigators wrote.

In quality of life measures, the intermittent therapy group had nonsignificantly better scores for functional domains (physical, role, and global health) and significantly better scores for symptoms, including hot flashes, desire for sexual activity, and urinary symptoms, the authors reported. Full testosterone recovery in the intermittent group occurred in 35% of the patients, while recovery to the trial entry threshold occurred in 79%, they said.

The authors concluded that their trial "raises provocative questions" and cautioned that their results "cannot be extrapolated to other intermittent-treatment schedules or disease characteristics."

The article did not address the apparent contradiction between the NCIC trial results and the findings of the Southwest Oncology Group (SWOG) 9346 trial reported earlier in the year at the ASCO annual meeting.

The latter trial randomized 3,040 patients with newly diagnosed hormone-sensitive metastatic prostate cancer with a PSA level of at least 5 ng/mL before androgen deprivation and a SWOG performance status of 0-2 to intermittent or continuous therapy. The investigators reported a 9% increase in the relative risk of death associated with intermittent therapy, which did not meet the prespecified criteria for noninferiority.

A secondary analysis of the SWOG 9346 data suggested that intermittent therapy was noninferior to CAD in patients with extensive disease but not minimal disease.

The NCIC trial was supported by grants from the Canadian Cancer Society, the U.S. National Cancer Institute, and Hoeschst Marion Roussel Canada Research. Dr. Crook disclosed no relevant financial conflicts. Study coinvestigators disclosed financial relationships with numerous companies.

View on The News

Which Men Actually Benefited?

In an accompanying editorial, Dr Oliver Sartor called the study by Dr. Crook and her colleagues "the most definitive study to date comparing intermittent versus continuous androgen-deprivation therapy in patients with nonmetastatic cancer."

He noted, however, that an important question remains unanswered: "It is still unclear which men with rising PSA levels needed treatment. This is a heterogeneous patient group, and only a minority of men might be expected to have clinical consequences from their rise in PSA level."

Considering the slow progression of prostate cancer in men, "which of these asymptomatic patients actually benefited from androgen-deprivation therapy?" he asked (N. Engl. J. Med. 2012;367:945-6).

DR. SARTOR is medical director of the Tulane Cancer Center and the C.E. and Bernadine Laborde Professor of Cancer Research at Tulane University, New Orleans He disclosed a financial relationship with Tolmar.